Endogenous p53 expression in human and mouse is not regulated by its 3'UTR

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• The TP53 gene encodes the p53 tumor suppressor, crucial for preventing cancer.
• Dysfunctional p53 is common in human cancers.
• Post-transcriptional regulation of TP53, particularly via its 3'UTR, is implicated in tumorigenesis.

Purpose of the Study:

• To investigate the role of the endogenous TP53 3'UTR in regulating p53 expression.
• To validate previously observed regulatory effects of the isolated TP53 3'UTR in a native context.

Main Methods:

• Utilized CRISPR/Cas9 gene editing to delete the 3'UTRs of human TP53 and mouse Trp53.
• Maintained endogenous mRNA processing in the genetic models.
• Employed reporter assays to assess gene expression regulation.

Main Results:

• The endogenous TP53 3'UTR does not regulate p53 mRNA or protein levels.
• Neither basal expression nor response to genotoxic stress is affected by the endogenous 3'UTR.
• While isolated 3'UTRs showed repression in reporter assays, the TP53 coding region exerted a stronger dominant-negative effect, masking 3'UTR contributions.

Conclusions:

• The endogenous TP53 3'UTR is not a significant regulator of p53 expression.
• Genetic models are essential for validating post-transcriptional regulatory effects in their native cellular environment.
• Findings challenge previous assumptions about 3'UTR-mediated regulation of TP53.